1. Field of the Invention (Technical Field)
The present invention provides both linear and cyclic peptides that are specific for one or more melanocortin receptors, and which may be used in the treatment of a wide variety of diseases.
2. Background Art
Melanocortin Receptors. A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues.
Peptides specific for melanocortin receptors have been reported to have a wide variety of biological activities, including effects upon pigmentation and steroidogenesis, known to be mediated by MSH (melanocyte stimulating hormone) and ACTH receptors. Several studies have documented the presence of melanotropin receptors on primary human melanoma cells (Tatro J B, Atkins M, Mier J W, et al. Melanotropin receptors demonstrated in situ in human melanoma. J Clin Invest, 85:1825-1832, 1990). Melanotropin receptors have been reported as markers for melanotic and amelanotic human melanoma tumors (Sharma S D, Granberry M E, Jiang J, et al. Multivalent melanotropic peptide and fluorescent macromolecular conjugates: new reagents for characterization of melanotropin receptors. Bioconjug Chem 5:591-601, 1994; Sharma S D, Jiang J, Hadley M E, et al. Melanotropic peptide-conjugated beads for microscopic visualization and characterization of melanoma melanotropin receptors. Proc Natl Acad Sci USA 93(24):13715-13720, 1996). In particular, the presence of MC1-R has been demonstrated in human melanoma cells by an antibody to MC1-R (Xia Y, Skoog V, Muceniece R, et al. Polyclonal antibodies against human melanocortin MC-1 receptor: Preliminary immunohistochemical localization of melanocortin MC1 receptor to malignant melanoma cells. European J Pharmacol 288:277-283, 1995). MC1-R is a G protein-coupled, 7-transmembrane receptor expressed in skin-cell melanocytes and shares some degree of homology with related receptors MC2-R, MC3-R, MC4-R and MC5-R. Each of these receptors can bind various peptide analogs that contain a common melanotropic pharmacophore, His-Phe-Arg-Trp (SEQ ID NO: 1), which describes the 6-9 sequence of the alpha-melanocyte stimulating hormone (α-MSH).
Prior to molecular characterization of the MC receptors, α-MSH analogs were labeled with the radioisotope Indium-111 and used in melanoma imaging studies (Wraight E P, Bard D R, Maughan T S, et al. The use of a chelating derivative of alpha melanocyte stimulating hormone for the clinical imaging of malignant melanoma. Brit J Radiology 65: 112-118, 1992; Bard D R, Knight C G and Page-Thomas D P. A chelating derivative of alpha-melanocyte stimulating hormone as a potential imaging agent for malignant melanoma. Brit J Cancer 62:919-922, 1990; Bard D R, Knight C G, Page-Thomas D P. Targeting of a chelating derivative of a short chain analogue of alpha-melanocyte stimulating hormone to Cloudman S91 melanomas. Biochem Soc Trans 18:882-883, 1990). Linear and cyclic disulfide-containing peptides have been identified and used for melanoma imaging and appear to be non-selective among MC receptors (Chen J and Quinn T P. Alpha melanocyte stimulating hormone analogues Tc-99 m/Re-188 labeling and their pharmacokinetics in malignant melanoma bearing mice. J Nucl Med 39: 222p, 1998; Giblin M F, Wang N, Hoffman T J, et al. Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination. Proc Natl Acad Sci USA 95(22):12814-12818, 1998). In later studies, the cyclic peptide reported by Giblin and coworkers was also found to localize in the brain (Wang N N, Giblin M F, Hoffman T J, et al. In vivo characterization of Tc-99m and Re-188 labeled cyclic melanotropin peptide analogues in a murine melanoma model. J Nucl Med 39: 77p, 1998 and corresponding poster presentation at the 45th Society of Nuclear Medicine Meeting, Toronto, June 1998). It has been recently reported that the response of human melanocytes to UV radiation is mediated by α-MSH induced activation of the cAMP pathway through the MC1-R (Im S, Moro O, Peng F, et al. Activation of the cyclic AMP pathway by alpha-melanotropin mediates the response of human melanocytes to ultraviolet B radiation. Cancer Res 58: 47-54, 1998).
MC4-R is also a G protein-coupled, 7-transmembrane receptor, but is believed to be expressed primarily in the brain. Inactivation of this receptor by gene targeting has been reported to result in mice with the maturity-onset obesity syndrome that is associated with hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar D, Lynch C A, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141, 1997). MC4-R is a molecular target for therapeutic intervention in energy homeostasis.
Alpha-MSH has been described as a potent anti-inflammatory agent in all major forms of inflammation (Star R A, Rajora N, Huang J, Stock R C, Catania A, and Lipton J M. Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte stimulating hormone. Proc Natl Acad Sci USA 92:8016-8020, 1995; Getting S J, and Perretti M. MC3-R as a novel target for antiinflammatory therapy. Drug News and Perspectives 13:19-27, 2000). Implication of both MC1-R and MC3-R receptors in anti-inflammatory processes has been stressed. In particular, the activation of these MC receptors by melanocortin receptor agonists has been reported to inhibit the expression of nitric oxide synthase and subsequent nitric oxide production.
Significant work has been done in determining the structure of melanocortin receptors, including both the nucleic acid sequences encoding for the receptors and the amino acid sequences constituting the receptors. See, for example, International Patent Application Nos. PCT/US98/12098 and PCT/US99/16862 and U.S. Pat. No. 5,994,087. A large number of ligands specific for melanocortin receptors, both agonists and antagonists, have also been developed. See, for example, International Patent Application Nos. PCT/US00/16396, commonly owned with this application and with common inventors (metallopeptides specific for MC receptors); PCT/US98/03298 (iodo group-containing melanocortin receptor-specific linear peptide); PCT/GB99/01388 (MC1-R specific linear peptides); PCT/GB99/01195 (MC3-R, MC4-R and MC5-R specific cyclic peptides); PCT/US99/04111 (MC1-R specific peptide antagonists for melanoma therapy); PCT/US99/09216 (isoquinoline compounds as melanocortin receptor ligands); PCT/US99/13252 (spiropiperdine derivatives as melanocortin receptor agonists); and U.S. Pat. No. 6,054,556 (cyclic lactam peptides as MC1-R, MC3-R, MC4-R and MC5-R antagonists). In addition, a large number of patents teach various methods of screening and determining melanocortin receptor-specific compounds, as for example International Patent Application Nos. PCT/US97/15565, PCT/US98/12098 and PCT/US99/16862 and U.S. Pat. Nos. 5,932,779 and 5,994,087.
In general, compounds specific for MC1-R are believed to be useful for treatment of melanoma, including use as radiotherapeutic or drug delivery agent, and as diagnostic imaging agents, particularly when labeled with a diagnostic radionuclide. Compounds specific for MC3-R, MC4-R or MC5-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and other treatment of other food intake and metabolism-related purposes. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used as agents for treatment of sexual dysfunction, including male erectile dysfunction. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used to regulate blood pressure, heart rate and other neurophysiologic parameters. Other melanocortin receptor peptides can be used as tanning agents, to increase melanin production, such as peptides that are MC1-R agonists. Compounds specific for MC1-R and MC3-R may be useful in regulation of inflammatory processes.
There remains a significant need for ligands with high specificity for discrete melanocortin receptors, as well as ligands or compounds that are either agonists or antagonists of specific melanocortin receptors. High affinity peptide ligands of melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as agonists or antagonists. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity peptide ligands of melanocortin receptors can be used to regulate cytokine activity.